FTO ameliorates learning and memory impairment by activating PI3K/AKT/mTOR signaling pathway in a neurodevelopmental model of schizophrenia

Background The pathogenesis of cognitive dysfunction in schizophrenia (SCZ) is still unclear, and m6A methylation may be involved in the neuropsychiatric diseases. The aim of this study was to investigate the effect of m6A methylation on learning and memory impairment induced by a neurodevelopmental model of SCZ. Methods Perinatal NMDA receptor antagonist combined with post-weaning social isolation (MK-SI) was used to construct a neural development model of SCZ. FTO adeno-associated virus (AAV) was injected into the hippocampus by stereotaxic technique. Then, it is evaluated by a series of behavioral tests. Brain tissue was analyzed by m6A dot blot, LC-MS/MS, qRT-PCR, western blot, tissue staining, MeRIP-seq, and colorimetry. Results Our results showed that FTO mediates m6A modification in the hippocampus of MK-SI mice, leading to learning and memory impairment. AAV9 FTO knockdown (FTO-KD) aggravated learning and memory impairment induced by MK-SI model. In contrast, AAV9 FTO overexpression (FTO-OE) reversed these effects. In addition, FB23-2 inhibited the reversal effect of FTO-OE in MK-SI mice, further confirming the important role of FTO in MK-SI-induced learning and memory impairment. Next, using high-throughput sequencing analysis, we found that the PI3K/AKT/mTOR signaling pathway may play a key role. In addition, the expression of the apoptotic protein Bax and the pro-apoptotic protein Bcl-2 were regulated by FTO. Conclusions In summary, the demethylase FTO mediated m6A modification to induce learning and memory impairment, highlighting the important role played by FTO in cognitive dysfunction in the MK-SI model.